Most patients who experience End Stage Renal Disease (ESRD) can benefit from kidney transplantation. The initial series of kidney transplants were performed in the 1950s in the USA and France and between identical twins. The introduction of potent immunosuppressive regimens, human leukocyte antigen (HLA)-typing for matching of recipients with donors, and cross matching (testing of recipient's serum against donor's cells for the presence of preformed antibodies) in the 1960s and 1970s made it possible to extend kidney transplantation to unrelated living donors and organs from deceased donors. The short-term outcomes of renal grafts have steadily improved since the early transplants with the refinement of immunosuppressive regimens, HLA compatibility, and a better understanding of when and how immunosuppressive drugs can be used to manage the health of the recipient and function of the graft. See, Opelz et al. Collaborative Transplant Study. Rev Immunogenet. 1(3):334-42 (1999); Angaswamy et al., Human Immunology 74(11):1478-85 (2013); Leventhal et al., J Am Soc Nephrol. 24(9):1376-85 (2013).
Despite these advances, data collected across the USA shows that 50% of kidney allografts fail within ten years of transplantation (Handbook of clinical transplantation. 4th edition ed. Danovitch G M, editor.: Lippincott Williams & Wilkins; 2009). Hence, yet uncharacterized genomic loci may influence donor/recipient compatibility.
Kidney transplant recipients suffer from a number of complications. Many renal transplant recipients experience an episode of acute cellular rejection (ACR), when the immune system of the recipient targets the transplanted donor organ. Adjusting the patient's immunosuppressive regiment may control episodes of ACR. Many transplant patients develop chronic rejection/chronic allograft nephropathy (CAN), which manifest itself in the graft by interstitial fibrosis and tubular atrophy (IF/TA) and a decline in graft function over time. ACR and CAN are routinely diagnosed by histopathological analysis of graft biopsies. While ACR is mostly a reversible adverse event, CAN, at the present time, is a relentlessly progressive condition for which no treatment is available. CAN progression is associated with loss of graft function, which eventually leads to graft loss. Chronic allograft nephropathy is poorly understood, and explains more than 50% of kidney graft losses.
Past studies have demonstrated the importance of HLA-mismatches on graft outcome, leading to important clinical strategies for graft allocation in many countries, including the U.S. As these strategies developed, it has become clearer that HLA mismatches represent only a component, albeit an important component, of the mismatches between donor and recipient. This suggests that mismatch at other loci in the genome, even remote from the HLA locus, may play a role influencing graft outcome. Indeed, fully HLA-matched kidney grafts may still develop acute cellular rejection as well as chronic allograft nephropathy, and more importantly every transplant, including recipients of fully HLA matched transplants need to be treated with chronic/maintenance immunosuppressive therapy to prevent rejection.
Hence, improved methods for matching donor organs to recipients are needed.